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Oxidative damage–induced inflammation initiates age-related macular degeneration

Nature Medicine volume 14, pages 194–198 (2008)Cite this article

Abstract

Oxidative damage and inflammation are postulated to be involved in age-related macular degeneration (AMD). However, the molecular signal(s) linking oxidation to inflammation in this late-onset disease is unknown. Here we describe AMD-like lesions in mice after immunization with mouse serum albumin adducted with carboxyethylpyrrole, a unique oxidation fragment of docosahexaenoic acid that has previously been found adducting proteins in drusen from AMD donor eye tissues1 and in plasma samples2 from individuals with AMD. Immunized mice develop antibodies to this hapten, fix complement component-3 in Bruch's membrane, accumulate drusen below the retinal pigment epithelium during aging, and develop lesions in the retinal pigment epithelium mimicking geographic atrophy, the blinding end-stage condition characteristic of the dry form of AMD. We hypothesize that these mice are sensitized to the generation of carboxyethylpyrrole adducts in the outer retina, where docosahexaenoic acid is abundant and conditions for oxidative damage are permissive. This new model provides a platform for dissecting the molecular pathology of oxidative damage in the outer retina and the immune response contributing to AMD.

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Figure 1: CEP antigen and CEP-specific antibody titers in immunized mice.
Figure 2: Relationship between pathology and CEP-specific antibody titer in the short-term immunization mice.
Figure 3: C3d localization in the outer eye wall of the short-term immunization mice.
Figure 4: Light and electron microscopy of the RPE–Bruch's membrane interface with quantitative comparisons.

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Acknowledgements

J.G.H. and V.L.P. designed and initiated the experiments. L.L. and R.G.S. prepared the CEP-MSA and CEP-BSA. R.L.U., V.L.P., K.G.S. and X.Y. immunized the mice. K.G.S. and X.Y. performed the protein chemistry and ELISA assays, as well as managing the day-to-day maintenance of the mice. M.E.R. and J.G.H. performed all of the histological and electron microscopic analysis. V.L.B. performed the confocal microscopy. J.G.H. analyzed all of the data and wrote the manuscript. R.G.S., R.L.U. and V.L.P. made critical comments and suggestions for revisions of the manuscript in response to the reviewers.

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Authors and Affiliations

  1. Department of Ophthalmology, Cole Eye Institute (i31), Cleveland Clinic Lerner College of Medicine, Cleveland, 44195, Ohio, USA

    Joe G Hollyfield, Vera L Bonilha, Mary E Rayborn, Xiaoping Yang, Karen G Shadrach, Rafael L Ufret & Victor L Perez

  2. Department of Chemistry, Case Western Reserve University, Cleveland, 44106, Ohio, USA

    Liang Lu & Robert G Salomon

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  1. Joe G Hollyfield
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Contributions

Supported by the State of Ohio Biomedical Research and Technology Transfer Program, a Research Center Grant from the Foundation Fighting Blindness, and a Challenge Grant from Research to Prevent Blindness. The project was also supported by grants R56EY10240, R01EY014240, R24EY015638 (J.G.H.), R21EY017153 (V.L.B.), R01GM21249 (R.G.S.) and K08EY014912 (V.L.P.) from the US National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the US National Eye Institute of the National Institutes of Health. We thank J.W. Crabb for valuable discussions, B. Anand-Apte for critical comments on the manuscript, N.S. Peachey for help with the statistical comparisons, R.L. Fairchild for providing the Rag-deficient mice, Y. Li for help with the histology, K. Sayanagi and T. Yakamoto for the fundus photography and A. Vasanji for developing the image-analysis algorithm used to define the areas of sub-RPE deposits.

Corresponding authors

Correspondence to Joe G Hollyfield or Victor L Perez.

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Competing interests

The mouse model for age-related macular degeneration described in this study is protected for commercialization by the Cleveland Clinic. J.G.H., R.G.S. and V.L.P. are the inventors.

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Supplementary Figs. 1–7 and Supplementary Table 1 (PDF 1014 kb)

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Hollyfield, J., Bonilha, V., Rayborn, M. et al. Oxidative damage–induced inflammation initiates age-related macular degeneration. Nat Med 14, 194–198 (2008). https://doi.org/10.1038/nm1709

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